Chimeric Protein Targets PSMA-Overexpressing Cells via dsRNA Binding

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Solution Overview

Problem

Current therapies for castration-resistant prostate cancer (CRPC) are ineffective in eradicating tumors due to genomic instability and resistance, with few targeted therapies available, and no PSMA-targeted therapies are clinically approved despite PSMA's promising therapeutic potential.

Innovation Solution

Development of a chimeric recombinant protein comprising a double-stranded RNA (dsRNA) binding domain and a prostate-specific membrane antigen (PSMA) targeting moiety, which selectively delivers dsRNA to PSMA-overexpressing cells, inducing apoptosis and immune responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional targeted therapies are used against genomically unstable tumor cells, then some tumor cells are killed, but the tumors eventually develop resistance and evade therapy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidduration of therapeutic effect

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The invention segments the therapeutic approach by using dsRNA to target multiple genes simultaneously, rather than relying on a single targeted pathway. This multi-gene targeting strategy prevents tumor cells from developing resistance through single mutations, as the dsRNA can silence multiple oncogenes or critical genes involved in tumor survival and progression.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The chimeric protein construct combines multiple functions: it includes a targeting domain for PSMA-specific recognition, a dsRNA binding domain for cargo attachment, and the dsRNA itself for gene silencing. This multi-functional design allows a single agent to perform targeted delivery, genetic silencing, and potential immune activation, addressing both the need for specific targeting and durable therapeutic effect.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If targeted therapies are applied to heterogeneous tumor subpopulations, then some subpopulations are affected, but other subpopulations remain untreated and tumor cannot be eradicated

Engineering Contradiction:

Improvecoverage of tumor subpopulationsVSAvoidtumor eradication capability

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The dsRNA component can be designed to target multiple genes that are critical across different tumor subpopulations, providing a universal mechanism that affects diverse cell types within the heterogeneous tumor. By silencing essential genes required for tumor cell survival rather than targeting subpopulation-specific markers, the therapy can eradicate the entire tumor including all subpopulations.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Measurement precision

If PSMA-targeted therapies are developed, then selective targeting of prostate cancer cells is achieved, but delivery of therapeutic cargo to the target cells remains challenging

Engineering Contradiction:

Improvetargeting specificityVSAvoidcomplexity of therapeutic construct

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The invention merges the PSMA-targeting function with the dsRNA delivery function into a single chimeric protein construct. The targeting domain and dsRNA binding domain are fused into one molecule, simplifying the delivery system while maintaining high targeting specificity. This unified construct eliminates the need for separate targeting and cargo delivery components, reducing overall system complexity.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric protein acts as an intermediary that bridges the PSMA target and the dsRNA therapeutic cargo. It contains a PSMA-binding domain for specific recognition and a dsRNA-binding domain for cargo attachment, mediating the selective delivery of dsRNA to prostate cancer cells expressing PSMA on their surface.

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The chimeric protein effectively kills PSMA-overexpressing cells, induces cytokine secretion, and triggers immune-mediated bystander effects, demonstrating potential for treating CRPC by selectively targeting and destroying tumor cells.

Implementation Method 1

a double stranded RNA (dsRNA) binding domain

Methodology Applied

Scientific EffectdsRNA binding:

Implementation Method 2

a target binding moiety that binds to prostate surface membrane antigen (PSMA)

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 3

selectively delivers dsRNA to PSMA-overexpressing cells, inducing apoptosis and immune responses

Methodology Applied

Scientific EffectApoptosis induction:

Implementation Method 4

induces cytokine secretion, and triggers immune-mediated bystander effects

Methodology Applied

Scientific EffectCytokine secretion:

Data Source

PatentUS11912747B2Chimeric proteins for targeting dsRNA

Publication Date: 2024.02.27 TARGIMMUNE THERAPEUTICS AG

AI summary

Described herein are recombinant chimeric proteins comprising a double stranded RNA (dsRNA) binding domain and a cancer-cell targeting domain for targeting of dsRNA to cancer cells. Methods of use of the described chimeric proteins are also provided herein.